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We herein developed a new ICD inducer VC@cLAV, which would induce strong ICD through elevating ROS in cancer cells for the immunotherapy of metastatic tumors while acting as an anti-oxidant in non-cancer cells for cytoprotection.

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (

Cu-mediated chemodynamic therapy (CDT) has attracted prominent attention owing to its advantages of pH independence and high efficiency comparing to Fe-mediated CDT, while the application of Cu-based CDT agents was impeded due to the high copper consumption caused by the metabolism loss of copper and the resultant potential toxicity. Herein, we developed a new copper-mediated CDT agent with extremely low Cu usage by anchoring copper on cross-linked lipoic acid nanoparticles (Cu@cLAs). After endocytosis into tumor cells, the Cu@cLAs were dissociated into LA and dihydrolipoic acid (DHLA) (reduced form of LA) and released Cu2+ and Cu+ (oxidized form of Cu2+), the two redox couples recycled each other in cells to achieve the efficient killing of cancer cells by delaying metabolic loss and increasing the ROS level of tumor cells. The self-recycling was confirmed in cells by the sustained high Cu/DHLA content and persistent ROS generation process. The antitumor study based on the MCF-7/R nude mice gave the Cu@cLAs a tumor inhibitory rate up to 77.9% at the copper of 0.05 mg kg−1, the first dosage reported so far lower than that of normal serum copper (0.83 ± 0.21 mg kg−1). This work provides not only a new promising clinical strategy for the copper excessive use in copper-mediated CDT, but also gives a clue for other metal mediated disease therapies with the high metal consumption.

A membrane-lytic mechanism-based nanodrug is developed for drug-resistant tumor therapy by anchoring the small-molecule quaternary ammonium salt (QAS) on cross-linked (R)-(+)-lipoic acid nanoparticles (cLANs). The anchoring of QAS on the nanoparticle avoids the direct attack of long alkyl chains to the cell membrane under physiological conditions, while after entering tumor cells, the QAS is released from the dissociated cLANs, migrates to the phospholipid bilayer via electrostatic interaction, and destroys the cell membrane by the puncture of long alkyl chains. Since the QAS is designed to finally be hydrolyzed to amino acid betaine and food additive cetanol and the cLANs degrade to dihydrolipoic acid (DHLA, reduced form of dietary antioxidant lipoic acid in cells), the QAS@cLANs hold superior biosafety. In addition to the drug-resistant tumors, the QAS@cLANs demonstrate significant inhibition of metastatic tumors. This work provides not only a general and clinic-promising treatment for the refractory tumors but also opens a door for the medicinal use of QAS.

Inspired by a plant leaf, a slippery liquid-infused porous surface (SLIPS) exhibits attractive nonwetting and self-cleaning abilities. However, rigorous requirements for the infused liquid layer and its inevitable loss limit its practical use. Here, we propose a model structure defined as a non-SLIPS by introducing solid nanostructures covered with a discontinuous lubricant film. This non-SLIPS tuned by solid wettability achieves the excellent self-cleaning feature with a small sliding angle comparable to the counterpart of a typical SLIPS. This sliding angle α* can be further reduced to a saturated plateau by a slight enhancement of hydrophobicity of the solid nanostructures. Interestingly, the sliding velocity remains almost constant for all of these non-SLIPS samples at a given tilt angle, independent of solid wettability. We formulate the slippery mechanism by defining an energy barrier responsible for the sliding initiation on the non-SLIPS. This energy barrier of the non-SLIPS is correlated, with a qualitative agreement, to the molecular adsorption on the solid nanostructures. The antibiological contamination is confirmed for this non-SLIPS, indicating its excellent self-cleaning ability. The findings suggest that the new surfaces, even with the gradual depletion of the infused oil layer, exhibit the nondegradation of the self-cleaning performance.

The retinal pigment epithelium (RPE) is a monolayer of polarized pigmented epithelial cells, located between the choroid and neuroretina in the retina. Multiple functions, including phagocytosis, nutrient/metabolite transportation, vitamin A metabolism, etc., are conducted by the RPE on a daily basis. RPE cells are terminally differentiated epithelial cells with little or no regenerative capacity. Loss of RPE cells results in multiple eye diseases leading to visual impairment, such as age-related macular degeneration. Therefore, the establishment of an in vitro culture model of primary RPE cells, which more closely resembles the RPE in vivo than cell lines, is critical for the characteristic and mechanistic studies of RPE cells. Considering the fact that the source of human eyeballs is limited, we create a protocol to culture primary porcine RPE cells. By using this protocol, RPE cells can be easily dissociated from adult porcine eyeballs. Subsequently, these dissociated cells attach to culture dishes/inserts, proliferate to form a confluent monolayer, and quickly re-establish key features of epithelial tissue in vivo within 2 wks. By qRT-PCR, it is demonstrated that primary porcine RPE cells express multiple signature genes at comparable levels with native RPE tissue, while the expressions of most of these genes are lost/highly reduced in human RPE-like cells, ARPE-19. Moreover, the immunofluorescence staining shows the distribution of tight junction, tissue polarity, and cytoskeleton proteins, as well as the presence of RPE65, an isomerase critical for vitamin A metabolism, in cultured primary cells. Altogether, we have developed an easy-to-follow approach to culture primary porcine RPE cells with high purity and native RPE features, which could serve as a good model to understand RPE physiology, study cell toxicities, and facilitate drug screenings.

Objective To evaluate the variation characteristics of systolic right intraventricular pressure differences (IVPDs) and right intraventricular pressure gradients (IVPGs) in patients with atrial fibrillation(AF) and normal left ventricular ejection fraction (LVEF) by relative pressure imaging (RPI) based on vector flow mapping(VFM),and to investigate their application value in right ventricular function in patients with normal LVEF AF. Methods Thirty-one patients with normal LVEF AF were selected as normal LVEF AF group，and twenty healthy volunteers were selected as control group.Clinical data and echocardiographic images were collected, and conventional left and right ventricular diameter, area, volume and systolic function parameters were measured.IVPDs and IVPGs in isovolumic contraction（IC）, early systole(ES) and late systole(LS) were obtained by the VFM technique.The correlation between the IVPDs and IVPGs in the three systolic time phases and the conventional ultrasound parameters was analyzed between the normal LVEF AF group and the control group. Results The systolic IVPDs and IVPGs in the normal LVEF AF group were significantly lower than those in the control group. Correlation analysis showed that ES-IVPGs and IC-IVPGs in patients with normal LVEF AF were positively correlated (PPPConclusions The patients with normal LVEF AF had a systolic right ventricular hemodynamics disorder, resulting in decreased IVPDs and IVPGs in each systolic phase. With a more pronounced decrease in IVPGs during IC which can be used as a potential new index to assess right ventricular hemodynamic changes in patients with normal LVEF AF.

As the most common subtype in ovarian malignancies, high-grade serous ovarian cancer (HGSOC) made less therapeutic progress in past decades due to the lack of effective drug-able targets. Herein, an effective linoleic acid (LA) and glucosamine (GlcN) hybrid (LA-GlcN) was synthesized for the treatment of HGSOC. The GlcN was introduced to recognize the glucose transporter 1 (GLUT 1) overexpressed in tumor cells to enhance the uptake of LA-GlcN, and the unsaturated LA was employed to trigger ferroptosis by iron-dependent lipid peroxidation. Since the iron content of HGSOC was ∼5 and 2 times, respectively, higher than that of the normal ovarian cells and low-grade serous ovarian cancer cells, these excess irons make them a good target to enhance the ferroptosis of LA-GlcN. The in vitro study demonstrated that LA-GlcN could selectively kill HGSOC cells without affecting normal cells; the in vivo study revealed that LA-GlcN at the dose of 50 mg kg

Long non-coding RNA musculin antisense RNA 1 (lncRNA MSC-AS1) has been recognized as an oncogene in pancreatic cancer, hepatocellular carcinoma, nasopharyngeal carcinoma, and renal cell carcinoma. However, the functional significance of MSC-AS1 and its underlying mechanism in gastric cancer (GC) progression remain unclear. In this study, we demonstrated that the expression of MSC-AS1 in GC tissues was significantly higher than that in non-tumor tissues. Moreover, the elevated level of MSC-AS1 was detected in GC cells (MKN-45, AGS, SGC-7901, and MGC-803) compared to normal GES-1 gastric mucosal cells. The cancer genome atlas (TCGA) data further indicated that the high level of MSC-AS1 was closely correlated with advanced tumor stage and poor prognosis of GC. Next, we revealed that MSC-AS1 knockdown inhibited the proliferation, glucose consumption, lactate production, and pyruvate production of MGC-803 cells. Conversely, MSC-AS1 overexpression enhanced the proliferation and glycolysis of AGC cells. Mechanistically, modulating MSC-AS1 level affected the expression of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), but did not impact the levels of hexokinase 2 (HK2) and pyruvate kinase M2 (PKM2) in GC cells. Based on this, we reversed the MSC-AS1 knockdown-induced the inhibition of cell proliferation and glycolysis by restoring PFKFB3 expression in MGC-803 cells. In conclusion, MSC-AS1 facilitated the proliferation and glycolysis of GC cells by maintaining PFKFB3 expression.

The underlying mechanisms of complement activation in Stargardt disease type 1 (STGD1) and age-related macular degeneration (AMD) are not fully understood. Overaccumulation of all-trans-retinal (atRAL) has been proposed as the pathogenic factor in both diseases. By incubating retinal pigment epithelium (RPE) cells with atRAL, we showed that C5b-9 membrane attack complexes (MACs) were generated mainly through complement alternative pathway. An increase in complement factor B (CFB) expression as well as downregulation of complement regulatory proteins CD46, CD55, CD59, and CFH were observed in RPE cells after atRAL treatment. Furthermore, interleukin-1β production was provoked in both atRAL-treated RPE cells and microglia/macrophages. Coincubation of RPE cells with interleukin-1 receptor antagonist (IL1Ra) and atRAL ameliorated complement activation and downregulated CFB expression by attenuating both p38 and c-Jun N-terminal kinase (JNK) signaling pathways. Our findings demonstrate that atRAL induces an autocrine/paracrine IL-1/IL-1R signaling to promote complement alternative pathway activation in RPE cells and provide a novel perspective on the pathomechanism of macular degeneration.

When the ‘CO-releasing molecule-3’, CORM-3 (Ru(CO)3Cl(glycinate)), is dissolved in water it forms a range of ruthenium complexes. These are taken up by cells and bind to intracellular ligands, notably thiols such as cysteine and glutathione, where the Ru(II) reaches high intracellular concentrations. Here, we show that the Ru(II) ion also binds to DNA, at exposed guanosine N7 positions. It therefore has a similar cellular target to the anticancer drug cisplatin, but not identical, because Ru(II) shows no evidence of forming intramolecular crossbridges in the DNA. The reaction is slow, and with excess Ru, intermolecular DNA crossbridges are formed. The addition of CORM-3 to human colorectal cancer cells leads to strand breaks in the DNA, as assessed by the alkaline comet assay. DNA damage is inhibited by growth media containing amino acids, which bind to extracellular Ru and prevent its entry into cells. We conclude that the cytotoxicity of Ru(II) is different from that of platinum, making it a promising development target for cancer therapeutics.

Topoisomerase1 (TOP1)-mediated chromosomal breaks are endogenous sources of DNA damage that affect neuronal genome stability. Whether TOP1 DNA breaks are sources of genomic instability in Huntington’s disease (HD) is unknown. Here, we report defective 53BP1 recruitment in multiple HD cell models, including striatal neurons derived from HD patients. Defective 53BP1 recruitment is due to reduced H2A ubiquitination caused by the limited RNF168 activity. The reduced availability of RNF168 is caused by an increased interaction with p62, a protein involved in selective autophagy. Depletion of p62 or disruption of the interaction between RNAF168 and p62 was sufficient to restore 53BP1 enrichment and subsequent DNA repair in HD models, providing new opportunities for therapeutic interventions. These findings are reminiscent to what was described for p62 accumulation caused by C9orf72 expansion in ALS/FTD and suggest a common mechanism by which protein aggregation perturb DNA repair signaling.

A membrane-lytic mechanism-based nanodrug is developed for drug-resistant tumor therapy by anchoring the small-molecule quaternary ammonium salt (QAS) on cross-linked (

It is well-known that vesicles serve as an excellent delivery platform for hydrophilic drugs. However, there is still a lack of a general and effective platform for hydrophobic drug loading. We herein disclose that water-soluble cross-linked reverse vesicles (cRVs) constructed from anionic surfactant 1, a counterpart of normal vesicles, would be excellent vehicles for hydrophobic drugs, the drug loading content (DLC) for which arrived up to 21.1%, 19.8%, and 25.8%, respectively, for three anticancer drugs, paclitaxel, camptothecin, and carmofur. This represents a general drug carrier with high drug loading content for various hydrophobic drugs without the assistance of other external forces. In addition to drug loading superiority, the cRVs were also characterized by robust stability, specific stimulus response, easy postfunctionalization, and good biocompatibility and thus are promising candidates for drug delivery systems.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that manifests as cognitive deficits and memory decline, especially in old age. Several biomarkers have been developed to monitor AD progression. Given that the retina and brain share some similarities including features related to anatomical composition and neurological functions, the retina is closely associated with the progression of AD. Herein, we review the evidence of retinal dysfunction in AD, particularly at the early stage, together with the underlying molecular mechanisms. Furthermore, we compared the retinal pathologies of AD and other ophthalmological diseases and summarized potential retinal biomarkers measurable by existing technologies for detecting AD, providing insights for the future development of diagnostic tools.

Background Although miR-125b plays a crucial role in many human cancers. However, its function in heart failure (HF) remains unclear. Our study aimed to investigate its involvement in heart failure. Methods In this study, the mouse HF model was successfully constructed through transverse aortic constriction (TAC) operation. Changes in mRNA and protein levels in isolated myocytes and heart tissues were examined using qRT-PCR, Western blot and Immunohistochemical staining and immunofluorescent staining. Changes in cardiac functions were examined using ultrasound. Interactions between miR-125b and BAK1 was analyzed using the luciferase reporter assay. Cardiomyocyte apoptosis was evaluated using the TUNEL staining. Results We found that miR-125b expression was significantly downregulated in myocardial tissues of HF mice. Moreover, miR-125b upregulation in HF mice injected with agomir-125b efficiently ameliorated cardiac function. Further, miR-125b upregulation significantly decreased the protein levels of apoptosis-related makers c-caspase 3 and Bax, while increased Bcl-2 expression. In addition, BAK1 was identified as a direct target of miR-125b. As expected, BAK1 overexpression observably reversed the effect of agomir-125b on cardiac function and on the expression of apoptosis-related makers in the heart tissues of HF mice. Conclusions Taken together, miR-125b overexpression efficiently attenuated cardiac function injury of HF mice by targeting BAK1 through inhibiting cardiomyocyte apoptosis, suggesting that miR-125b/BAK1 axis might be a potential target for the diagnosis or treatment of HF.

The nonspecific toxicity of loaded drugs and the side effect of carriers are two obstacles that hinder the clinical development of anticancer nanodrugs. Herein, we developed a new nanodrug 3-(methylthio)-propanoate camptothecin (Pro-CPT) loaded with cross-linked (R)-(+)-lipoic acid nanoparticles (Pro-CPT@cLANs). The Pro-CPT is a pH-responsive prodrug of camptothecin (CPT) that can effectively reduce the systemic toxicity of CPT caused by premature release. The cLANs are nanoparticles with structural homology to (R)-(+)-lipoic acid (LA) that hold not only LA-like biocompatibility but also LA-like anticancer activity, which may further relieve the toxicity of loaded drugs by reducing their dosages through synergistic effects and precise drug release at the tumor sites. According to in vitro data, the IC of Pro-CPT@cLANs against HT29 cells was 0.12 μM, ∼2.5 times lower than that of free Pro-CPT (0.3 μM); in vivo data showed that the tumor inhibition rate (TIR) and survival rate (SR) of Pro-CPT@cLANs against HT29 tumor-bearing nude mice were up to 85.1% and 80%, respectively, also far better than those of free CPT at the same dosage (TIR: 46%, SR: 0%). The Pro-CPT@cLANs provide a simple and efficient strategy to surmount the two obstacles in the development of nanodrugs and hold potential in clinical utility.

Herein, a new nanodrug of azobenzene-functionalized interfacial cross-linked reverse micelles (AICRM) with 5-fluorouracil loading (5-FU@AICRM) is reported. Upon irradiation with 530 nm light in water, the surface azobenzenes of the nanoparticles change from polar cis-conformation to nonpolar trans-conformation, resulting in the aggregation of 5-FU@AICRM within minutes. Simultaneously, the conformation change unlocks hydrophilic 5-FU with a strong water immigration propensity, allowing them to spray out from the AICRM quickly. This fast release ensures a thorough release of the drug, before the aggregates are internalized by adjacent cells, making it possible to achieve deep tissue penetration. A study of in vivo anticancer activity in A549 tumor-bearing nude mice shows that the tumor inhibition rate (TIR) of 5-FU@AICRM is up to ≈86.2%, 31.6% higher than that of group without green light irradiation and 20.7% higher than that of carmofur (CF, a hydrophobic analog of 5-FU)-loaded AICRM (CF@AICRM), in which CF is released slowly under light irradiation because of its hydrophobicity. Fast drug release upon nanodrug aggregation provides a good solution for balancing the contradiction of "aggregation and penetration" in tumor treatment with nanodrugs.

Magnetic materials with high mobilities are intriguing subjects of research from both fundamental and application perspectives. Based on first-principle calculations, we investigate the physical properties of the already synthesized $A\mathrm{MnBi}$ ($A=\mathrm{K}$, Rb, Cs) family materials. We show that these materials are antiferromagnetic (AFM), with N\'eel temperatures above 300 K. They contain AFM ordered Mn layers, while the interlayer coupling changes from ferromagnetic (FM) for KMnBi to AFM for RbMnBi and CsMnBi. We find that these materials are narrow gap semiconductors. Owing to the small effective mass, the electron carrier mobility can be very high, reaching up to ${10}^{5}\phantom{\rule{4pt}{0ex}}{\mathrm{cm}}^{2}/(\mathrm{V}\phantom{\rule{0.16em}{0ex}}\mathrm{s}$) for KMnBi. In contrast, the hole mobility is much suppressed, typically lower by two orders of magnitude. We further study their two-dimensional (2D) single layer structures, which are found to be AFM with fairly high mobility $\ensuremath{\sim}{10}^{3}\phantom{\rule{4pt}{0ex}}{\mathrm{cm}}^{2}/(\mathrm{V}\phantom{\rule{0.16em}{0ex}}\mathrm{s})$. Their N\'eel temperatures can still reach room temperature. Interesting, we find that the magnetic phase transition is also accompanied by a metal-insulator phase transition, with the paramagnetic metal phase possessing a pair of nonsymmorphic-symmetry-protected 2D spin-orbit Dirac points. Furthermore, the magnetism can be effectively controlled by the applied strain. When the magnetic ordering is turned into FM, the system can become a quantum anomalous Hall insulator with gapless chiral edge states.

Hierarchical hollow urchin-like ternary composite which consists of hollow graphene spheres(HGRs), flowerlike molybdenum disulfide(MoS2) and manganese dioxide(MnO2) nanoflakes has been successfully synthesized by chemical vapor deposition(CVD) and two-step hydrothermal methods. The HGRs/MoS2/MnO2 composite was characterized by X-ray diffraction(XRD), field emission scanning electron microscopy(FESEM) and transmission electron microscopy(TEM), and its electrochemical properties were evaluated by cyclic voltammetry(CV), galvanostatic charge/discharge(GCD), and electrochemical impedance spectroscopy(EIS) measurements. The experimental results demonstrated that the specific capacitance of HGRs/MoS2/MnO2 composite is 608 F g−1 at a current density of 1 A·g−1, which is far higher than that of HGRs/MoS2 (300 F g−1) and HGRs/MnO2 (344 F g−1). In addition, 89.3% of the original capacitance of HGRs/MoS2/MnO2 composite is retained after 2500 cycles at a current density of 2 A·g−1, which keeps better cycle stability compared to HGRs/MnO2 composite. The excellent electrochemical performance can be ascribed to the synergistic effect of HGRs, flowerlike MoS2 and MnO2 nanoflakes. Flowerlike MoS2 as an ion buffer layer is beneficial to rapid ion diffusion and transportation from MnO2 into interior HGRs. Furthermore, HGRs/MoS2 composite as a three-dimensional(3D) matrix alleviates the volume change during charge/discharge cyclical process. The well-structured HGRs/MoS2/MnO2 composite with high performance has a great potential for advanced supercapacitors(SCs) applications.

Aims To investigate the work stress among Chinese nurses who are supporting Wuhan in fighting against Coronavirus Disease 2019 (COVID‐19) infection and to explore the relevant influencing factors. Background The COVID‐19 epidemic has posed a major threat to public health. Nurses have always played an important role in infection prevention, infection control, isolation, containment and public health. However, available data on the work stress among these nurses are limited. Methods A cross‐sectional survey. An online questionnaire was completed by 180 anti‐epidemic nurses from Guangxi. Data collection tools, including the Chinese version of the Stress Overload Scale (SOS) and the Self‐rating Anxiety Scale (SAS), were used. Descriptive single factor correlation and multiple regression analyses were used in exploring the related influencing factors. Results The SOS (39.91 ± 12.92) and SAS (32.19 ± 7.56) scores of this nurse group were positively correlated (r = 0.676, p

Disrupted clearance of all-trans-retinal (atRAL), a component of the visual (retinoid) cycle in the retina, may cause photoreceptor atrophy in autosomal recessive Stargardt disease (STGD1) and dry age-related macular degeneration (AMD). However, the mechanisms underlying atRAL-induced photoreceptor loss remain elusive. Here, we report that atRAL activates c-Jun N-terminal kinase (JNK) signaling at least partially through reactive oxygen species production, which promoted mitochondria-mediated caspase- and DNA damage-dependent apoptosis in photoreceptor cells. Damage to mitochondria in atRAL-exposed photoreceptor cells resulted from JNK activation, leading to decreased expression of Bcl2 apoptosis regulator (Bcl2), increased Bcl2 antagonist/killer (Bak) levels, and cytochrome c (Cyt c) release into the cytosol. Cytosolic Cyt c specifically provoked caspase-9 and caspase-3 activation and thereby initiated apoptosis. Phosphorylation of JNK in atRAL-loaded photoreceptor cells induced the appearance of γH2AX, a sensitive marker for DNA damage, and was also associated with apoptosis onset. Suppression of JNK signaling protected photoreceptor cells against atRAL-induced apoptosis. Moreover, photoreceptor cells lacking Jnk1 and Jnk2 genes were more resistant to atRAL-associated cytotoxicity. The Abca4(−/−) Rdh8(−/−) mouse model displays defects in atRAL clearance that are characteristic of STGD1 and dry AMD. We found that JNK signaling was activated in the neural retina of light-exposed Abca4(−/−)Rdh8(−/−) mice. Of note, intraperitoneal administration of JNK–IN-8, which inhibits JNK signaling, effectively ameliorated photoreceptor degeneration and apoptosis in light-exposed Abca4(−/−)Rdh8(−/−) mice. We propose that pharmacological inhibition of JNK signaling may represent a therapeutic strategy for preventing photoreceptor loss in retinopathies arising from atRAL overload.

Free all-trans-retinal (atRAL) and retinal pigment epithelium (RPE) lipofuscin are both considered to play etiological roles in Stargardt disease and age-related macular degeneration. A2E and all-trans-retinal dimer (atRAL-dimer) are two well characterized bisretinoid constituents of RPE lipofuscin. In this study, we found that, after treatment of primary porcine RPE (pRPE) cells with atRAL, atRAL-dimer readily formed and accumulated in a concentration- and time-dependent manner, but A2E was barely detected. Cell-based assays revealed that atRAL, the precursor of atRAL-dimer, significantly altered the morphology of primary pRPE cells and decreased cell viability at a concentration of 80 μm regardless of light exposure. By contrast, atRAL-dimer was not cytotoxic and phototoxic to primary pRPE cells. Compared with atRAL and A2E, atRAL-dimer was more vulnerable to light, followed by the generation of its photocleaved products. Moreover, we observed the presence of atRAL-dimer in reaction mixtures of atRAL with porcine rod outer segments (ROS), RPE/choroid, or neural retina. Taken together, we here proposed an alternative metabolic/antidotal pathway of atRAL in the retina: atRAL that evades participation of the visual (retinoid) cycle undergoes a condensation reaction to yield atRAL-dimer in both ROS and RPE. Translocation of atRAL, all-trans N-retinylidene–phosphatidylethanolamine (NR-PE), atRAL-dimer, and photocleavage products of atRAL-dimer from ROS into RPE is accomplished by phagocytosing shed ROS on a daily basis. Without causing damage to RPE cells, light breaks up total atRAL-dimer within RPE cells to release low-molecular-weight photocleavage fragments. The latter, together with ROS-atRAL-dimer photocleavage products, may easily move across membranes and thereby be metabolically eliminated.

The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its mechanisms remain elusive. Here, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase was identified as one of the major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in the release of cytochrome c from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME in the mitochondria revealed that GSDME was likely to penetrate mitochondrial membranes in photoreceptor cells after atRAL exposure. ABC (subfamily A, member 4) and all-trans-retinol dehydrogenase 8 are two key proteins responsible for clearing atRAL in the retina. Abca4−/−Rdh8−/− mice exhibit serious defects in atRAL clearance upon light exposure and serve as an acute model for dry AMD and STGD1. We found that N-terminal fragment of GSDME was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4−/−Rdh8−/− mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4−/−Rdh8−/−Gsdme−/− mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repressing GSDME may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.

Retinal pigment epithelium (RPE) cell apoptosis arising from all-trans-retinal (atRAL) is in close contact with the etiology of dry age-related macular degeneration (AMD) and autosomal recessive Stargardt's disease (STGD1), but its underlying mechanisms remain elusive. In this study, we reported that c-Jun N-terminal kinase (JNK) activation facilitated atRAL-induced apoptosis of RPE cells. Reactive oxygen species production and endoplasmic reticulum stress were identified as two of major upstream events responsible for activating JNK signaling in atRAL-loaded RPE cells. Inhibiting JNK signaling rescued RPE cells from apoptosis induced by atRAL through attenuating caspase-3 activation leading to poly-ADP-ribose polymerase (PARP) cleavage, and DNA damage response. Abca4